(R)-2-Acetamido-N-benzyl-3-methoxypropionamide, also known as lacosamide, is effective in the treatment of pain, osteoarthritis, migraine and epilepsy. Lacosamide has the structure given below (I)

The product is described and claimed in WO9733861. This document describes different synthetic methods. Starting with (D)-serine, this amino acid is converted to (R)-2-acetamino-2-N-benzyl-3-hydroxy-propionamide by coupling with benzylamine (BnNH2) followed by acetylation using acetic anhydride (Ac2O). This is then methylated using methyl iodide (Mel) and silver oxide (Ag2O) to produce the required product (Scheme 1).

Alternatively, (D)-serine is first acetylated, the resulting N-acetyl amino acid coupled with benzylamine, under conditions described in Journal of the American Chemical Society (1967), 89, pp 5012-7 via a mixed anhydride, and finally methylated with a combination of methyl iodide and silver oxide (Scheme 2). In both cases the intermediates are difficult to isolate from the reaction solutions and are difficult to handle.

In a further alternative approach to prepare lacosamide described in WO9733861, the amino group of (D)-serine is first protected with a protecting group, such as a carboxybenzyl-group (Cbz). This is followed by ‘O’-methylation and subsequent reactions to the desired product, eg benzylamination at the carboxylic acid function, de-protection, and acetylation of the amine function (Scheme 3). This route is also described in U.S. Pat. No. 6,048,899; which additionally provides a similar approach with inversion of steps 2 and 3, i. e. the amide formation is performed prior to the methylation.

However, all those processes suffer from use of large quantities of silver, which is both expensive and must be removed from the final product. Additionally partial racemisation of the expensive chiral centre is observed in several cases, which lowers yields. Recently WO2010107993 (whose United States equivalent is United States Patent Publication No. 2010/240926A1) has been published. This describes a similar route to that in Scheme 3 except that (R)-N-benzyl-2-(benzyloxycarbonylamino)-3-hydroxy-propionamide is methylated using dimethyl sulfate at temperatures between −15° C. and 25° C. By operating at lower temperatures it is claimed that undesired methylation at the nitrogen groups is reduced.
A further process for the production of lacosamide has also been described in EP2067765 A1 (whose United States equivalent is United States Patent Publication No. 2009/143472A1). This uses the very bulky trityl-protecting group for protection of the serine, thereby minimising the potential for racemisation at the chiral centre during the subsequent methylation reaction (Scheme 4).

Although the use of expensive silver oxide is no longer necessary using trityl as protecting group, the necessity to perform many transformations on “tritylated” materials, with a very high molecular mass, makes the process less effective from an economic point of view.
Alternatively WO 2006037574 (whose United States equivalents are United States Patent Publication Nos. 2008/027137A1 and 2011/1303350A1) also describes a process for lacosamide production starting from (D)-serine. In this process, the amine group is protected with a boc (tert-butoxy-carbonyl-) group, and the methylation of the boc protected amino acid is carried out in the presence either of a phase transfer catalyst plus base or an organolithium reagent. After methylation, the boc protected (D)-methoxy-serine is worked through to the lacosamide via benzylamination, de-protection, and acetylation.
Recently WO2010052011 has been published which describes routes to racemic lacosamide (a mixture of (R)- plus (S)-2-acetamido-N-benzyl-3-methoxypropionamide). The racemic mixture is then separated using simulated bed chromatography (SMB) with a chiral phase, and the unwanted enantiomer is then racemised and recycled (Scheme 5).
